In collaboration with the groups of Drs. Paul Bieniasz, Theodora Hatziioannou, and Jeff Lifson, we have developed a simian-tropic HIV-1 (stHIV-1) that is approximately 90% HIV-1 in genetic origin and replicates in pig-tailed macaques. The first-generation X4-tropic stHIV-1 is capable of persistent, low-level replication in vivo but with no resultant pathogenesis. In more recent work, R5-tropic versions of stHIV-1 show a similar persistent, albeit not robust, level of replication in infected animals. There is an ongoing collaborative effort to enhance replication of R5-tropic stHIV-1 through further genetic modification as well as in vivo animal passaging of the virus. In addition, in relation to our basic science studies, we are examining whether HIV-1 CA, in macaque cells, triggers innate immune responses due to recognition or uncoating of the PIC in the cytoplasm. We have recently recruited a new postdoctoral fellow to aid in our stHIV-1 related studies. Our current aims in this work include: 1) In vivo, serial passage of R5-tropic stHIV-1; 2) Characterization of R5-tropic stHIV-1 tissue distribution and pathogenesis; 3) Characterization of innate immune responses in macaque cells in response to HIV-1 CA in stHIV-1 during infection. [Corresponds to KewalRamani Project 3 in the October 2011 site visit report of the HIV Drug Resistance Program]